Patients with type 2 diabetes mellitus (DM) appear to have a small increased risk of colorectal cancer. Treatment of DM can include diet therapy, insulin, and or oral medications. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of transcription factors whose activities are regulated by high affinity binding of small lipophilic ligands such as steroid hormones. A new class of diabetic drugs, the thiazolidinediones (TZDs), binds to the, /subtype of the PPARs. A unique feature of these drugs is improvement in insulin sensitivity. Colonic epithelial cells express high levels of PPARgamma, protein. Prior in vitro and in vivo studies have suggested that PPARgamma may influence the development and progression from normal colon mucosa to benign adenomatous polyps and eventually to invasive cancer. The majority of these studies suggest a potential chemoprotective effect of TZD PPARgamma ligands. For example, animal models of carcinogenesis demonstrate reduced production of aberrant crypt foci and intestinal tumors in the presence of PPARgamma ligands. Despite widespread use of TZDs to treat type 2 DM, data on the effect of these compounds on colonic neoplasia in humans are lacking. However, our preliminary data suggests that 1 year or greater exposure to TZDs may reduce the risk of colorectal cancer among patients with type 2 DM. The proposed study is a retrospective case-control study nested within the cohort of diabetic patients from Kaiser Permanente Northern California who have been in the care of Kaiser physicians since before the marketing of TZDs in the US. From this cohort, approximately 4,000 patients who have undergone colonoscopy between 1999 and 2005 will be categorized into 1 of 3 groups according to the findings at colonoscopy: advanced adenomatous neoplasia, early adenomatous neoplasia, and no adenomatous neoplasia. In addition, approximately 6,000 patients who have undergone serial sigmoidoscopies will be categorized according to the presence or absence of adenomatous neoplasia in the distal colon on the second sigmoidoscopy. Use of TZDs prior to the colonoscopy or second sigmoidoscopy will be compared among the groups. As such, we will assess the effect of the compounds on the progression from normal mucosa to adenomatous neoplasia. Our results will allow us to translate the existing in vitro and in vivo observations to the intact human colon and could lead to further chemoprevention strategies.